Discovery and Optimization of Dihydroquinolin-2(1H)-ones as Novel Highly Selective and Orally Bioavailable Phosphodiesterase 5 Inhibitors for the Treatment of Pulmonary Arterial Hypertension

Article

Author: Zhang, Bei ; Zhao, Pei-Liang ; Chen, Jun-Wei ; Wang, Gang ; Zou, Zhong-Kai ; Tan, Wen-Ming ; Li, Wei-En ; Wu, Wei-Pei ; Liang, Jing-Nan ; Ruan, Xiao-Hong ; Cai, Jian-Fan

Phosphodiesterase 5 (PDE5) is a cGMP-specific hydrolytic enzyme and widely distributed in versatile tissues. PDE5 has been identified as a valid therapeutic target for treating erectile dysfunction and pulmonary arterial hypertension (PAH). Herein, a hit-to-lead structural optimizations were performed on the PDE1 inhibitor 10c, leading to compound 14b possessing great potency against PDE5A (IC₅₀ = 3 nM) with high selectivity over PDE1, PDE2, PDE3, PDE4, PDE7, PDE8, PDE9, PDE10, and PDE11 by more than 1125-fold, and remarkable safety properties. Furthermore, oral administration of 14b (5.0 mg/kg) exerted much better pharmacodynamics effects on both mPAP (mean pulmonary artery pressure) and RVHI (index of right ventricle hypertrophy) than sildenafil citrate (10.0 mg/kg) in a monocrotaline-induced PAH rat model. Overall, these results proposed a novel highly selective PDE5 inhibitor 14b which could serve as a potential candidate for treatment of PAH.

01 Jun 2022·The Lancet NeurologyQ1 · MEDICINE

Approach and management to patients with neurological disorders reporting sexual dysfunction

Q1 · MEDICINE

Review

Author: Amarenco, Gérard ; Hentzen, Claire ; Del Popolo, Giulio ; Musco, Stefania ; Panicker, Jalesh N

Sexual difficulties are common in patients with neurological disorders, and different domains of sexual function-desire, arousal, orgasm, and ejaculation-can be affected. Advances in the past 7 years in structural and functional neuroimaging have contributed to a greater understanding of the neural pathways involved in the regulation of sexual functions in health and disease, and this increased knowledge might help with development of future therapeutic strategies. A comprehensive assessment of patients includes history taking-covering the different domains of dysfunction, and primary, secondary, and tertiary contributory factors-as well as clinical examination in select patients (ie, patients for whom an associated non-neurological cause for sexual dysfunction is suspected). Investigations, such as assessment of associated cardiovascular risk factors, might also be indicated in specific situations. PDE5A inhibitors and intracavernosal injections of the prostaglandin alprostadil are effective for treating erectile dysfunction; however, options for managing other domains of sexual dysfunction in men and women remain poor. Research into different domains of sexual dysfunction is likely to lead to additional therapeutic strategies in the future.

11 Apr 2019·Current Topics in Medicinal ChemistryQ4 · MEDICINE

Novel Pyrazolo[4, 3-c]Quinolin-3-One Derivatives as PDE5A Inhibitors

Q4 · MEDICINE

Article

Author: Bhakuni, Rashmi ; Kirubakaran, Sivapriya ; Shaik, Althaf ; Agarwal, Harshit K

Background: PDE5A is a phosphodiesterase which specifically hydrolyzes the cGMP to GMP. It takes part in several physiological and pathological pathways and is considered an important drug target. Currently, PDE5 inhibitors (ex; Sildenafil, Tadalafil) available in the market are not only being used for the treatment of erectile dysfunction but at the same time, they are also in clinical trials being investigated as anticancer agents. Materials & Methods: In this work, we have examined pyrazolo [4,3-c]quinolin-3-ones as PDE5A inhibitors. Pyrazolo [4,3-c]quinolin-3-ones are the class of tricyclic heterocyclic derivatives having a variety of therapeutically interesting drug candidates known for their anti-inflammatory, anti-viral, anti-anxiety and anti-cancer activity. Therefore, synthetic methods providing access to pyrazolo [4, 3-c] quinolin-3-ones are immensely valuable. Here, we are reporting a simple but efficient route for the synthesis of novel 8–morpholino-2-aryl – 2, 5-dihydro-3H-pyrazolo [4, 3-c] quinolin-3-one derivatives. Results: Further, molecular docking studies of synthesized compounds with human PDE5A protein showed that all the compounds exhibited good docking score in comparison with known inhibitors. In addition, all the synthesized molecules were evaluated against HCT116 cell lines for their antitumor activity. Conclusion: Among all the synthesized compounds, compound 5a, 5d, and 6e showed better cytotoxicity. Thus, these derivatives can be studied as potential inhibitors of PDE5A.

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Indication	Highest Phase	Country/Location	Organization	Date
Pulmonary Arterial Hypertension	Preclinical	China	Southern Medical University	05 Dec 2024

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